Based on prior evidence that stimulation of β2-adrenergic receptor (β2AR) in dendritic cells enhanced IL-10 and reduced IL-6 production, Mohammadpour et al. investigated the effect of β2AR inhibition or knockout on graft-vs-tumor (GVT) and graft-vs-host disease (GVHD) in a model of CD8+ T cell hematopoietic cell transplant. Loss of β2AR signaling increased the immunogenic properties of host DC cells via reduced STAT3 phosphorylation, resulting in increased CD8+ T cell reconstitution, increased memory T cells, and improved GVT without enhanced GVHD.

Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that beta2-adrenergic receptor (beta2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a beta2AR blocker significantly increases the GVT effect of donor CD8(+) T cells by decreasing tumor burden without increasing graft-versus-host disease. beta2AR-deficient host mice have significantly increased effector memory and central memory CD8(+) T cells and improved reconstitution of T cells, including CD4(+)Foxp3(+) regulatory T cells. Notably, beta2AR deficiency induces increased CD11c(+) DC development. Also, beta2AR-deficient bone marrow-derived DCs induce higher CD8(+) T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that beta2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host beta2AR signaling in suppressing T cell reconstitution and GVT activity.

Author Info: (1) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY (2) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY Department of Microbiology

Author Info: (1) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY (2) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201. (3) Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; and. (4) Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY (5) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY (6) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; Xuefang.Cao@RoswellPark.org. Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201.

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